ES2556460T3 - Novel derivatives of methylcyclohexane and their uses - Google Patents

Novel derivatives of methylcyclohexane and their uses Download PDF

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ES2556460T3
ES2556460T3 ES11829552.6T ES11829552T ES2556460T3 ES 2556460 T3 ES2556460 T3 ES 2556460T3 ES 11829552 T ES11829552 T ES 11829552T ES 2556460 T3 ES2556460 T3 ES 2556460T3
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pyridin
carboxylic acid
methylcyclohexane
synthesis
nmr
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Sung Jin Bae
Han Ju Yi
Sun Gwan Hwang
Mo Ses Jeong
Yeo Jin Yoon
Sang Mi Chae
Joo Young Park
Eun Ju Ryu
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SK Biopharmaceuticals Co Ltd
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Abstract

Un compuesto seleccionado del grupo que consiste en un derivado de metilciclohexano representado por la Fórmula I siguiente y una sal, un solvato y un hidrato del derivado de metilciclohexano farmacéuticamente aceptables y una combinación de los mismos.**Fórmula** en la que Ar se selecciona entre el grupo que consiste en fenilo, piridina y piridin-N-óxido, cada uno de los cuales está sustituido con uno o más sustituyentes idénticos o diferentes seleccionados del grupo que consiste en un átomo de hidrógeno, un alquilo C1 a C6 lineal o ramificado, halógeno, un alcoxi C1 a C6 lineal o ramificado y trifluorometilo; X es O, (C>=O)O, NR1(C>=O)O, NH, (C>=O)NH o O(C>=O)NH y R1 es H o CH3; Y es CH2, O o N-R2; R2 es H o CH3; A es O o NH; B es CH o N; y m es un número entero entre 0 y 2 y n es 0 o 1.A compound selected from the group consisting of a methylcyclohexane derivative represented by Formula I below and a pharmaceutically acceptable salt, solvate and hydrate of the methylcyclohexane derivative and a combination thereof. ** Formula ** in which Ar is select from the group consisting of phenyl, pyridine, and pyridine-N-oxide, each of which is substituted with one or more identical or different substituents selected from the group consisting of a hydrogen atom, a linear C1 to C6 alkyl, or branched, halogen, a linear or branched C1 to C6 alkoxy and trifluoromethyl; X is O, (C> = O) O, NR1 (C> = O) O, NH, (C> = O) NH or O (C> = O) NH and R1 is H or CH3; Y is CH2, O or N-R2; R2 is H or CH3; A is O or NH; B is CH or N; and m is an integer between 0 and 2 and n is 0 or 1.

Description

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imagen12image12

(m, 3H), 3,91 (s, 2H), 3,40~3,23 (m, 4H), 3,01~2,91 (m, 3H), 2,11~1,51 (m, 9H), 1,42~1,05 (m, 4H) (m, 3H), 3.91 (s, 2H), 3.40 ~ 3.23 (m, 4H), 3.01 ~ 2.91 (m, 3H), 2.11 ~ 1.51 (m , 9H), 1.42 ~ 1.05 (m, 4H)

Ejemplo 11: Síntesis del éster 4-(1-oxi-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico Example 11: Synthesis of the pyrrolidine-1-carboxylic acid 4- (1-oxy-pyridin-4-ylmethylcarbamoyloxy) -cyclohexylmethyl ester

imagen13image13

Un compuesto objetivo (393 mg, 52 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-4-il)metilamina. An objective compound (393 mg, 52% yield) was obtained in the same manner as in Example 1, except that C- (1-oxy-pyridin-4-yl) methylamine was used as the starting material.

10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,14-8,13 (d, 2H, J = 6,3 Hz), 7,29-7,21 (d, 2H, J = 6,3 Hz), 5,95 (s, 1H), 4,58-4,52 (m, 1H) , 3,91-3,85 (m, 2H), 3,36-3,30 (m, 5H), 3,00-2,50 (m, 1H), 2,0 (m, 2H), 1,83-1,82 (m, 7H), 1,591,53 (m, 2H), 1,31-1,21 (m, 4H), 1,14-1,3 (m, 2H) 10 1H NMR (500 MHz, CDCl3), ppm (δ): 8.14-8.13 (d, 2H, J = 6.3 Hz), 7.29-7.21 (d, 2H, J = 6.3 Hz), 5.95 (s, 1H), 4.58-4.52 (m, 1H), 3.91-3.85 (m, 2H), 3.36-3.30 (m , 5H), 3.00-2.50 (m, 1H), 2.0 (m, 2H), 1.83-1.82 (m, 7H), 1,591.53 (m, 2H), 1, 31-1.21 (m, 4H), 1.14-1.3 (m, 2H)

15 Ejemplo 12: Síntesis del éster 4-(1-oxi-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico Example 12: Synthesis of the pyrrolidine-1-carboxylic acid 4- (1-oxy-pyridin-3-ylmethylcarbamoyloxy) -cyclohexylmethyl ester

imagen14image14

20 Un compuesto objetivo (325 mg, 43 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-3-il)-metilamina. An objective compound (325 mg, 43% yield) was obtained in the same manner as in Example 1, except that C- (1-oxy-pyridin-3-yl) -methylamine was used as the starting material.

RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,21-8,13 (m, 1H), 7,26-7,24 (m, 3H), 5,16-4,59 (m, 1H), 4,35 (m, 1H), 3,923,91 (m, 1H), 3,41-3,33 (m, 2H), 2,8-2,4 (m, 1H), 1,87-1,84 (m, 4H), 1,63 (m, 4H), 1,35-1,11 (m, 2H) 1H NMR (500 MHz, CDCl3), ppm (δ): 8.21-8.13 (m, 1H), 7.26-7.24 (m, 3H), 5.16-4.59 (m , 1H), 4.35 (m, 1H), 3,923.91 (m, 1H), 3.41-3.33 (m, 2H), 2.8-2.4 (m, 1H), 1, 87-1.84 (m, 4H), 1.63 (m, 4H), 1.35-1.11 (m, 2H)

25 Ejemplo 13: Síntesis del éster 4-(1-oxi-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico Example 13: Synthesis of the pyrrolidine-1-carboxylic acid 4- (1-oxy-pyridin-2-ylmethylcarbamoyloxy) -cyclohexylmethyl ester

imagen15image15

Un compuesto objetivo (264 mg, 35 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-2-il)metilamina. An objective compound (264 mg, 35% yield) was obtained in the same manner as in Example 1, except that C- (1-oxy-pyridin-2-yl) methylamine was used as the starting material.

14 14

RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,29-8,19 (d, 1H, J = 6,3 Hz), 7,38-7,37 (m, 1H), 7,25-7,18 (m, 2H), 6,236,21 (m, 1H), 4,48-4,45 (m, 3H), 3,85-3,82 (m, 2H), 3,32-3,25 (m, 4H), 1,97-1,93 (m, 2H), 1,81-1,74 (m, 6H), 1,581,82 (m , 2H), 1,27-1,20 (m, 4H) 1H NMR (500 MHz, CDCl3), ppm (δ): 8.29-8.19 (d, 1H, J = 6.3 Hz), 7.38-7.37 (m, 1H), 7, 25-7.18 (m, 2H), 6.236.21 (m, 1H), 4.48-4.45 (m, 3H), 3.85-3.82 (m, 2H), 3.32- 3.25 (m, 4H), 1.97-1.93 (m, 2H), 1.81-1.74 (m, 6H), 1,581.82 (m, 2H), 1.27-1, 20 (m, 4H)

Ejemplo 14: Síntesis del éster 4-(6-cloro-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico Example 14: Synthesis of the 4- (6-chloro-pyridin-2-ylmethylcarbamoyloxy) -cyclohexylmethyl ester of pyrrolidin-1-carboxylic acid

imagen16image16

10 Un compuesto objetivo (491 mg, 62 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-2-il)metilamina. An objective compound (491 mg, 62% yield) was obtained in the same manner as in Example 1, except that C- (6-chloro-pyridin-2-yl) methylamine was used as the starting material.

RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,67~7,60 (m, 1H), 7,26~7,21 (m, 2H), 5,61~5,55 (m, 1H), 4,64~4,53 (m, 1H), 4,44 (d, 2H, J = 5,7 Hz), 3,90 (d, 2H, J = 6,0 Hz), 3,42~3,28 (m, 4H), 2,10~1,99 (m, 2H), 1,92~1,84 (m, 5H), 15 1,67~1,55 (m, 2H), 1,40~1,03 (m, 4H) 1H NMR (300 MHz, CDCl3), ppm (δ): 7.67 ~ 7.60 (m, 1H), 7.26 ~ 7.21 (m, 2H), 5.61 ~ 5.55 (m , 1H), 4.64 ~ 4.53 (m, 1H), 4.44 (d, 2H, J = 5.7 Hz), 3.90 (d, 2H, J = 6.0 Hz), 3 , 42 ~ 3.28 (m, 4H), 2.10 ~ 1.99 (m, 2H), 1.92 ~ 1.84 (m, 5H), 15 1.67 ~ 1.55 (m, 2H ), 1.40 ~ 1.03 (m, 4H)

Ejemplo 15: Síntesis del éster 4-(6-metil-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1ácido carboxílico Example 15: Synthesis of the 4- (6-methyl-pyridin-2-ylmethylcarbamoyloxy) -cyclohexylmethyl ester of carboxylic acid pyrrolidin-1

imagen17image17

Un compuesto objetivo (451 mg, 60 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-metil-piridin-2-il)metilamina. An objective compound (451 mg, 60% yield) was obtained in the same manner as in Example 1, except that C- (6-methyl-pyridin-2-yl) methylamine was used as the starting material.

25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,58~7,50 (m, 1H), 7,10~7,01 (m, 2H), 5,84~5,79 (m, 1H), 4,65~4,55 (m, 1H), 4,44 (d, 2H, J = 5,1 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,10 (m, 4H), 2,53 (s, 3H), 2,15~1,99 (m, 2H), 1,95~1,75 (m, 5H), 1,73~1,52 (m, 2H), 1,44~1,03 (m, 4H) 1 H NMR (300 MHz, CDCl3), ppm (δ): 7.58 ~ 7.50 (m, 1H), 7.10 ~ 7.01 (m, 2H), 5.84 ~ 5.79 ( m, 1H), 4.65 ~ 4.55 (m, 1H), 4.44 (d, 2H, J = 5.1 Hz), 3.90 (d, 2H, J = 6.3 Hz), 3.42 ~ 3.10 (m, 4H), 2.53 (s, 3H), 2.15 ~ 1.99 (m, 2H), 1.95 ~ 1.75 (m, 5H), 1, 73 ~ 1.52 (m, 2H), 1.44 ~ 1.03 (m, 4H)

Ejemplo 16: Síntesis del éster 4-(2-cloro-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin30 1-carboxílico Example 16: Synthesis of the 1- (2-chloro-pyridin-4-ylmethylcarbamoyloxy) -cyclohexylmethyl ester of 1-carboxylic acid

imagen18image18

Un compuesto objetivo (523 mg, 66 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-4-il)metilamina. An objective compound (523 mg, 66% yield) was obtained in the same manner as in Example 1, except that C- (2-chloro-pyridin-4-yl) methylamine was used as the starting material.

15 fifteen

RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,33 (d, 1H, J = 5,1 Hz), 7,25 (s, 1H), 7,14 (d, 1H, J = 4,8 Hz), 5,33~5,26 (m, 1H), 4,65~4,54 (m, 1H), 4,36 (d, 2H, J = 6,3 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,41~3,29 (m, 4H), 2,18~1,99 (m, 2H), 1,95~1,77 (m, 6H), 1,70~1,52 (m, 1H), 1,43~1,03 (m, 4H) 1H NMR (300 MHz, CDCl3), ppm (δ): 8.33 (d, 1H, J = 5.1 Hz), 7.25 (s, 1H), 7.14 (d, 1H, J = 4.8 Hz), 5.33 ~ 5.26 (m, 1H), 4.65 ~ 4.54 (m, 1H), 4.36 (d, 2H, J = 6.3 Hz), 3, 90 (d, 2H, J = 6.3 Hz), 3.41 ~ 3.29 (m, 4H), 2.18 ~ 1.99 (m, 2H), 1.95 ~ 1.77 (m, 6H), 1.70 ~ 1.52 (m, 1H), 1.43 ~ 1.03 (m, 4H)

Ejemplo 17: Síntesis del éster 4-(6-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico Example 17: Synthesis of the 4- (6-chloro-pyridin-3-ylmethylcarbamoyloxy) -cyclohexylmethyl ester of pyrrolidin-1-carboxylic acid

imagen19image19

10 Un compuesto objetivo (435 mg, 55 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-3-il)-metilamina. An objective compound (435 mg, 55% yield) was obtained in the same manner as in Example 1, except that C- (6-chloro-pyridin-3-yl) -methylamine was used as the starting material.

RMN de 1H (300 MHz, CDCl3), ppm (~): 8,31 (s, 1H), 7,63 (d, 1H, J = 7,2 Hz), 7,30 (d, 1H, J = 8,4 Hz), 5,20~5,12 (m, 1H), 4,63~4,52 (m, 1H), 4,34 (d, 2H, J = 6,0 Hz), 3,90 (d, 2H, J = 6,6 Hz), 3,41~3,28 (m, 4H), 2,13~1,99 (m, 2H), 15 1,97~1,72 (m, 6H), 1,69~1,53 (m, 1H), 1,42~1,04 (m, 4H) 1H NMR (300 MHz, CDCl3), ppm (~): 8.31 (s, 1H), 7.63 (d, 1H, J = 7.2 Hz), 7.30 (d, 1H, J = 8.4 Hz), 5.20 ~ 5.12 (m, 1H), 4.63 ~ 4.52 (m, 1H), 4.34 (d, 2H, J = 6.0 Hz), 3, 90 (d, 2H, J = 6.6 Hz), 3.41 ~ 3.28 (m, 4H), 2.13 ~ 1.99 (m, 2H), 15 1.97 ~ 1.72 (m , 6H), 1.69 ~ 1.53 (m, 1H), 1.42 ~ 1.04 (m, 4H)

Ejemplo 18: Síntesis del éster 4-(2-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico Example 18: Synthesis of the 4- (2-Chloro-pyridin-3-ylmethylcarbamoyloxy) -cyclohexylmethyl ester of pyrrolidin-1-carboxylic acid

imagen20image20

Un compuesto objetivo (404 mg, 51 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-3-il)-metilamina. An objective compound (404 mg, 51% yield) was obtained in the same manner as in Example 1, except that C- (2-chloro-pyridin-3-yl) -methylamine was used as the starting material.

25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,34~8,28 (m, 1H), 7,75 (d, 1H, J = 6,6 Hz), 7,27~7,21 (m, 1H), 5,35~5,27 (m, 1H), 4,62~4,50 ( m, 1H), 4,42 (d, 2H, J = 6,6 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,28 (m, 4H), 2,15~1,77 (m, 8H), 1,74~1,50 (m, 1H), 1,46~1,02 (m, 4H) 1 H NMR (300 MHz, CDCl3), ppm (δ): 8.34 ~ 8.28 (m, 1H), 7.75 (d, 1H, J = 6.6 Hz), 7.27 ~ 7 , 21 (m, 1H), 5.35 ~ 5.27 (m, 1H), 4.62 ~ 4.50 (m, 1H), 4.42 (d, 2H, J = 6.6 Hz), 3.90 (d, 2H, J = 6.3 Hz), 3.42 ~ 3.28 (m, 4H), 2.15 ~ 1.77 (m, 8H), 1.74 ~ 1.50 ( m, 1H), 1.46 ~ 1.02 (m, 4H)

Ejemplo 19: Síntesis del éster del 4-(6-trifluorometil-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido 30 pirrolidin-1-carboxílico Example 19: Synthesis of the pyrrolidine-1-carboxylic acid 4- (6-trifluoromethyl-pyridin-3-ylmethylcarbamoyloxy) -cyclohexylmethyl ester

imagen21image21

16 16

imagen22image22

imagen23image23

imagen24image24

Ejemplo 29: Síntesis del éster 4-bencilcarbamoiloxi-ciclohexilmetílico del ácido 4-metil-piperazin-1carboxílico Example 29: Synthesis of 4-methyl-piperazine-1-carboxylic acid 4-benzylcarbamoyloxy-cyclohexylmethyl ester

imagen25image25

5 Un compuesto objetivo (101 mg, 13 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que fueron utilizados como materiales de partida bencilamina y 1-metil-piperazina y el yoduro de metilo no se utilizó en el segundo paso. An objective compound (101 mg, 13% yield) was obtained in the same manner as in Example 1, except that benzylamine and 1-methyl-piperazine were used as starting materials and methyl iodide was not used in the second step.

10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 7,38~7,24 (m, 5H), 4,96 (sa, 1H), 4,65~4,54 (m, 1H), 3,92 (d, 2H, J = 6,4 Hz), 3,51~3,47 (m, 4H), 2,41~2,34 (m, 4H), 2,30 (s, 3H), 2,12~2,02 (m, 1H), 1,94~1,79 (m, 2H), 1,68~1,52 (m, 2H), 1,38~1,29 ( m, 2H), 1,20~1,09 (m, 2H) 10 1 H NMR (500 MHz, CDCl 3), ppm (δ): 7.38 ~ 7.24 (m, 5H), 4.96 (sa, 1H), 4.65 ~ 4.54 (m, 1H) , 3.92 (d, 2H, J = 6.4 Hz), 3.51 ~ 3.47 (m, 4H), 2.41 ~ 2.34 (m, 4H), 2.30 (s, 3H ), 2.12 ~ 2.02 (m, 1H), 1.94 ~ 1.79 (m, 2H), 1.68 ~ 1.52 (m, 2H), 1.38 ~ 1.29 (m , 2H), 1.20 ~ 1.09 (m, 2H)

Ejemplo 30: Síntesis del éster 4-(pirrolidin-1-carboniloximetil)-ciclohexílico del ácido piridin-2-carboxílico Example 30: Synthesis of the 4- (pyrrolidin-1-carbonyloxymethyl) -cyclohexyl ester of pyridine-2-carboxylic acid

15 fifteen

imagen26image26

A una solución de éster 4-hidroxi-ciclohexilmetílico del ácido pirrolidin-1-carboxílico (1 mmol) en cloruro de metileno (5 ml) se añadieron cloruro de picolinoílo (1,1 mmol) y trietilamina (1,5 mmol) y la mezcla resultante se agitó durante To a solution of 4-hydroxy-cyclohexylmethyl ester of pyrrolidin-1-carboxylic acid (1 mmol) in methylene chloride (5 ml) were added picolinoyl chloride (1.1 mmol) and triethylamine (1.5 mmol) and the resulting mixture was stirred for

20 16 horas a temperatura ambiente. La mezcla de reacción se diluyó con agua, seguido de par de veces de extracción con cloruro de metileno. La capa orgánica combinada se secó sobre sulfato de magnesio anhidro, se filtró y se concentró a presión reducida. El residuo se purificó por cromatografía en columna (gel de sílice, acetato de etilo), completando de este modo la preparación de un compuesto objetivo (233 mg, rendimiento del 70 %). 20 16 hours at room temperature. The reaction mixture was diluted with water, followed by a couple of times extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (233 mg, 70% yield).

25 RMN del 1H (300 MHz, CDCl3), ppm (δ): 8,80~8,76 (m, 1H), 8,15~8,11 (m, 1H), 7,90~7,80 (m, 1H), 7,50~7,45 (m, 1H), 5,08~4,98 (m, 1H ), 3,98 (d, 2H, J = 6,6 Hz), 3,43~3,33 (m, 4H), 2,17~2,08 (m, 2H), 1,99~1,83 (m, 5H), 1,81~1,53 (m, 3H), 1,20~1,08 (m, 3H) 1 H NMR (300 MHz, CDCl3), ppm (δ): 8.80 ~ 8.76 (m, 1H), 8.15 ~ 8.11 (m, 1H), 7.90 ~ 7.80 ( m, 1H), 7.50 ~ 7.45 (m, 1H), 5.08 ~ 4.98 (m, 1H), 3.98 (d, 2H, J = 6.6 Hz), 3.43 ~ 3.33 (m, 4H), 2.17 ~ 2.08 (m, 2H), 1.99 ~ 1.83 (m, 5H), 1.81 ~ 1.53 (m, 3H), 1 , 20 ~ 1.08 (m, 3H)

Los Ejemplos 31 a 33 siguientes se llevan a cabo cada uno de la misma manera que en el Ejemplo 30, excepto que 30 el material de partida utilizado era diferente del material de partida utilizado en el Ejemplo 30. The following Examples 31 to 33 are each carried out in the same manner as in Example 30, except that the starting material used was different from the starting material used in Example 30.

20 twenty

imagen27image27

imagen28image28

imagen29image29

imagen30image30

imagen31image31

imagen32image32

imagen33image33

imagen34image34

imagen35image35

imagen36image36

Ejemplo 13 Example 13
27,9 >50 27.9 > 50

Ejemplo 14 Example 14
21,7 22,3 21.7 22.3

Ejemplo 15 Example 15
19,9 19,4 19.9 19.4

Ejemplo 16 Example 16
27,9 10,8 27.9 10.8

Ejemplo 17 Example 17
29,5 12,5 29.5 12.5

Ejemplo 18 Example 18
5,7 18,3 5.7 18.3

Ejemplo 19 Example 19
11,1 13,8 11.1 13.8

Ejemplo 20 Example 20
50 37,9 fifty 37.9

Ejemplo 21 Example 21
15,9 44,8 15.9 44.8

Ejemplo 22 Example 22
35,8 21,7 35.8 21.7

Ejemplo 23 Example 23
28,6 >50 28.6 > 50

Ejemplo 24 Example 24
>50 >50 > 50 > 50

Ejemplo 25 Example 25
24,9 15,5 24.9 15.5

Ejemplo 26 Example 26
46,1 36,8 46.1 36.8

Ejemplo 27 Example 27
50,0 >50 50.0 > 50

Ejemplo 28 Example 28
>50 44,8 > 50 44.8

Ejemplo 29 Example 29
46,1 >50 46.1 > 50

Ejemplo 30 Example 30
>50 >50 > 50 > 50

Ejemplo 31 Example 31
>50 21,1 > 50 21.1

Ejemplo 32 Example 32
21,1 34,8 21.1 34.8

Ejemplo 33 Example 33
>50 >50 > 50 > 50

Ejemplo 34 Example 34
24,9 27,1 24.9 27.1

Ejemplo 35 Example 35
>50 50,0 > 50 50.0

Ejemplo 36 Example 36
>50 >50 > 50 > 50

Ejemplo 37 Example 37
46,1 >50 46.1 > 50

Ejemplo 38 Example 38
35,8 >50 35.8 > 50

Ejemplo 39 Example 39
>50 >50 > 50 > 50

Ejemplo 40 Example 40
>50 >50 > 50 > 50

Ejemplo 41 Example 41
50 >50 fifty > 50

Ejemplo 42 Example 42
50 >50 fifty > 50

Ejemplo 43 Example 43
10,5 12,0 10.5 12.0

Ejemplo 44 Example 44
21,7 16,8 21.7 16.8

Ejemplo 45 Example 45
9,9 7,5 9.9 7.5

Ejemplo 46 Example 46
32,0 26,3 32.0 26.3

Ejemplo 47 Example 47
13,1 21,1 13.1 21.1

Ejemplo 48 Example 48
13,5 10,2 13.5 10.2

Ejemplo 49 Example 49
12,0 10,2 12.0 10.2

Ejemplo 50 Example 50
5,7 14,2 5.7 14.2

Ejemplo 51 Example 51
50 >50 fifty > 50

Ejemplo 52 Example 52
22,3 >50 22.3 > 50

Ejemplo 53 Example 53
33,9 >50 33.9 > 50

Ejemplo 54 Example 54
48,7 >50 48.7 > 50

Ejemplo 55 Example 55
25,6 >50 25.6 > 50


Ejemplo 57: Prueba de alivio del dolor utilizando un modelo animal
Example 57: Pain relief test using an animal model

1) Modelo animal 5 Se adquirieron as ratas macho (Sprague-Dawley, 150-200 g, de 6 semanas de edad, Orient Bio Co., Ltd) y se aclimataron en una cámara de animales durante una semana. La cámara de animales se encendía y apagaba alternativamente a intervalos de 12 horas, con una temperatura de 22 a 25 ºC y una humedad relativa de 40-60 % y se suministró agua y alimento ad libitum a las ratas. 10 1) Animal model 5 Male rats (Sprague-Dawley, 150-200 g, 6 weeks old, Orient Bio Co., Ltd) were purchased and acclimatized in an animal chamber for one week. The animal chamber was switched on and off alternately at 12-hour intervals, with a temperature of 22 to 25 ° C and a relative humidity of 40-60% and water and food ad libitum were supplied to the rats. 10

31 31

imagen37image37

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